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Synlett 2025; 36(08): 1079-1085
DOI: 10.1055/a-2460-8054
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TfOH-Catalyzed Synthesis of Bis(pyrrolo[2,1-a]isoquinolinyl) methanes

Jing Zhou
,
Xue Sheng
,
Yu-Yi Pan
,
Hai-Lei Cui  ∗

We are grateful for the support provided for this study by the Science and Technology Research Program of Chongqing Municipal Education Commission (KJZD-K202201305) and the National Natural Science Foundation of China (21871035).
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Abstract

The synthesis of bis(pyrrolo[2,1-a]isoquinolinyl)methanes was achieved through TfOH-catalyzed sequential Friedel–Crafts alkylation of pyrrolo[2,1-a]isoquinoline and aldehyde. A series of highly functionalized bis(pyrrolo[2,1-a]isoquinolinyl)methane derivatives can be obtained in acceptable to excellent yields (11 examples, up to 96% yield). Interestingly, deformylation was observed when treating pyrrolo[2,1-a]isoquinoline-derived aldehyde and indole under the current reaction conditions. Furthermore, the replacement of aldehyde with isatin resulted in the formation of methylene-bridged dimeric pyrrolo[2,1-a]isoquinoline.

Key word

aldehyde - bis(pyrrolo[2,1-a]isoquinolinyl)methane - deformylation - pyrrolo[2,1-a]isoquinoline - TfOH

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-2460-8054.
  • Supporting Information


Publikationsverlauf

Eingereicht: 12. September 2024

Angenommen nach Revision: 04. November 2024

Accepted Manuscript online:
04. November 2024

Artikel online veröffentlicht:
04. Dezember 2024

© 2024. Thieme. All rights reserved

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  • References and Notes

  • 1 Present address: Guangdong Sanvochemical Industry Technology Co., Ltd., Zhongshan, Guangdong 528429, P. R. of China.
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  • 21 CCDC 2132856 (3a) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
  • 23 General Procedure for the Synthesis of Compounds 3 To a stirring solution of pyrrolo[2,1-a]isoquinoline 1 (0.2 mmol, 1.0 equiv) and aldehyde 2 (0.5 mmol, 2.5 equiv) in DMF (0.2 M, 0.5 mL), TfOH (4.4 μL, 0.05 mmol, 25 mol%) was added. The resulting reaction mixture was stirred at 150 °C (oil bath) under an air atmosphere for the indicated times shown in Schemes 2 and 3 (monitored by thin-layer chromatography). Then, the mixture was cooled to rt, diluted with DCM (2 mL), washed with water (2 × 2 mL). The organic phase was concentrated, and the residue was purified directly by the silica gel flash chromatography (hexane/EtOAc) to afford compound 3. Analytical Data for Typical Compounds
    Compound 3a     White solid, 66.3 mg, 96% (using 50 mol% of TfOH); purified by a silica gel flash chromatography (hexane/EtOAc, 97:3). 1H NMR (400 MHz, CDCl3): δ = 8.24 (d, J = 7.7 Hz, 2 H), 7.68 (s, 1 H), 7.56–7.38 (m, 14 H), 7.32–7.21 (m, 5 H), 7.19–7.13 (m, 2 H), 7.10 (ddd, J = 8.4, 7.1, 1.4 Hz, 2 H), 6.72 (d, J = 7.7 Hz, 2 H), 3.26 (s, 6 H). 13C NMR (100 MHz, CDCl3): δ = 166.7, 138.1, 136.6, 130.8, 130.4, 128.6, 128.6, 128.4, 127.4, 127.2, 127.1, 126.8, 126.5, 126.0, 125.6, 125.1, 122.9, 122.7, 118.9, 118.4, 112.9, 51.3, 39.9. HRMS (ESI): m/z [M + Na]+ calcd for C47H34N2NaO4 +: 713.2411; found: 713.2419. Compound 3b White solid, 19.9 mg, 28%; purified by a silica gel flash chromatography (hexane/EtOAc, 97:3). 1H NMR (400 MHz, CDCl3): δ = 8.21 (d, J = 7.6 Hz, 2 H), 7.63 (s, 1 H), 7.46 (ddd, J = 24.7, 10.3, 6.2 Hz, 14 H), 7.30–7.21 (m, 2 H), 7.13–7.02 (m, 6 H), 6.72 (d, J = 7.7 Hz, 2 H), 3.27 (s, 6 H), 2.32 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 166.7, 136.7, 135.0, 130.8, 130.4, 129.3, 128.5, 128.4, 127.4, 127.2, 127.1, 126.8, 126.6, 125.9, 125.5, 125.3, 122.9, 122.7, 118.9, 118.4, 112.8, 51.3, 39.5, 21.0. HRMS (ESI): m/z [M + Na]+ calcd for C48H36N2NaO4 +: 727.2567; found: 727.2560. Compound 3c Pale yellow solid, 40.6 mg, 56%; purified by a silica gel flash chromatography (hexane/EtOAc, 17:3). 1H NMR (400 MHz, CDCl3): δ = 8.19 (d, J = 7.6 Hz, 2 H), 7.58 (s, 1 H), 7.52–7.37 (m, 14 H), 7.26–7.22 (m, 2 H), 7.13–7.04 (m, 4 H), 6.85–6.79 (m, 2 H), 6.72 (d, J = 7.7 Hz, 2 H), 3.78 (s, 3 H), 3.28 (s, 6 H). 13C NMR (100 MHz, CDCl3): δ = 166.7, 158.6, 136.7, 130.7, 130.4, 130.1, 129.8, 128.4, 127.4, 127.2, 127.1, 126.8, 126.5, 125.9, 125.5, 125.4, 122.9, 122.6, 118.9, 118.4, 114.0, 112.9, 55.3, 51.3, 39.2. HRMS (ESI): m/z [M + Na]+ calcd for C48H36N2NaO5 +: 743.2516; found: 743.2524. Compound 3d White solid, 49.2 mg, 68%; purified by a silica gel flash chromatography (hexane/EtOAc, 97:3). 1H NMR (400 MHz, CDCl3): δ = 8.24 (d, J = 7.7 Hz, 2 H), 7.65 (s, 1 H), 7.50–7.39 (m, 14 H), 7.29–7.21 (m, 4 H), 7.15–7.06 (m, 4 H), 6.75 (d, J = 7.7 Hz, 2 H), 3.30 (s, 6 H). 13C NMR (100 MHz, CDCl3): δ = 166.7, 136.8, 136.5, 132.9, 130.7, 130.4, 130.0, 128.6, 128.4, 127.33, 127.26, 127.2, 126.8, 126.5, 126.1, 125.8, 124.5, 122.9, 122.4, 118.9, 118.3, 113.2, 51.4, 39.3. HRMS (ESI): m/z [M + Na]+ calcd for C47H33ClN2NaO4 +: 747.2021; found: 747.2018. Compound 3e White solid, 15.8 mg, 21%; purified by a silica gel flash chromatography (hexane/EtOAc, 17:3). 1H NMR (400 MHz, CDCl3): δ = 8.27 (d, J = 7.7 Hz, 2 H), 7.68 (s, 1 H), 7.53–7.39 (m, 16 H), 7.29–7.21 (m, 2 H), 7.19–7.07 (m, 2 H), 7.00 (d, J = 7.7 Hz, 1 H), 6.75 (d, J = 7.6 Hz, 2 H), 3.34 (s, 6 H). 13C NMR (100 MHz, CDCl3): δ = 166.8, 140.5, 136.5, 131.7, 130.8, 130.4, 130.3, 130.2, 128.4, 127.4, 127.3, 127.2, 126.8, 126.5, 126.1, 125.8, 124.2, 123.0, 122.6, 122.4, 119.0, 118.4, 113.2, 51.4, 39.5. HRMS (ESI): m/z [M + Na]+ calcd for C47H33BrN2NaO4 +: 791.1516; found: 791.1525. Compound 3h Yellow solid, 33.8 mg, 47%; purified by a silica gel flash chromatography (hexane/EtOAc, 17:3). 1H NMR (400 MHz, CDCl3): δ = 8.20 (d, J = 7.6 Hz, 2 H), 7.64 (s, 1 H), 7.51–7.35 (m, 4 H), 7.33–7.20 (m, 13 H), 7.18–7.05 (m, 4 H), 6.71 (d, J = 7.7 Hz, 2 H), 3.28 (s, 6 H), 2.47 (s, 6 H). 13C NMR (100 MHz, CDCl3): δ = 166.7, 136.7, 133.4, 130.5, 130.2, 129.2, 128.7, 128.6, 127.3, 127.1, 127.0, 126.7, 125.9, 125.6, 124.9, 122.9, 122.6, 119.0, 118.5, 112.8, 51.3, 40.0, 21.4. HRMS (ESI): m/z [M + Na]+ calcd for C49H38N2NaO4 +: 741.2724; found: 741.2733. Compound 3i Pale yellow solid, 34.9 mg, 46%; purified by a silica gel flash chromatography (hexane/EtOAc, 17:3). 1H NMR (400 MHz, CDCl3): δ = 8.19 (d, J = 7.6 Hz, 2 H), 7.64 (s, 1 H), 7.49–7.39 (m, 6 H), 7.36–7.20 (m, 7 H), 7.17–7.09 (m, 4 H), 7.05–6.97 (m, 4 H), 6.70 (d, J = 7.7 Hz, 2 H), 3.91 (s, 6 H), 3.28 (s, 6 H). 13C NMR (100 MHz, CDCl3): δ = 166.7, 158.8, 138.2, 131.8, 131.5, 128.6, 128.6, 127.3, 127.08, 127.06, 126.74, 126.65, 125.9, 125.8, 124.9, 122.9, 122.6, 118.6, 113.9, 112.8, 55.2, 51.4, 39.9. HRMS (ESI): m/z [M + Na]+ calcd for C49H38N2NaO6 +: 773.2622; found: 773.2625. Compound 3j White solid, 44.9 mg, 55%; purified by a silica gel flash chromatography (hexane/EtOAc, 9:1). 1H NMR (400 MHz, CDCl3): δ = 8.21 (d, J = 7.6 Hz, 2 H), 7.65 (s, 1 H), 7.56 (d, J = 8.2 Hz, 2 H), 7.48–7.43 (m, 2 H), 7.33–7.22 (m, 5 H), 7.18–7.14 (m, 4 H), 6.72 (d, J = 7.6 Hz, 2 H), 6.66 (d, J = 2.1 Hz, 2 H), 6.59–6.51 (m, 4 H), 3.83–3.80 (m, 12 H), 3.31 (s, 6 H). 13C NMR (100 MHz, CDCl3): δ = 166.7, 160.74, 160.69, 138.5, 138.0, 128.7, 128.6, 128.4, 127.3, 127.2, 127.1, 126.7, 126.3, 126.0, 125.5, 124.9, 123.2, 122.6, 118.6, 118.3, 112.9, 108.6, 108.3, 99.8, 55.4, 51.4, 39.8. HRMS (ESI): m/z [M + Na]+ calcd for C51H42N2NaO8 +: 833.2833; found: 833.2843. Compound 3k Yellow solid, 36.4 mg, 48%; purified by a silica gel flash chromatography (hexane/EtOAc, 17:3). 1H NMR (400 MHz, CDCl3): δ = 8.18 (d, J = 7.7 Hz, 2 H), 7.67 (s, 1 H), 7.52–7.33 (m, 11 H), 7.33–7.23 (m, 6 H), 7.19–7.10 (m, 4 H), 6.73 (d, J = 7.7 Hz, 2 H), 3.28 (s, 6 H). 13C NMR (100 MHz, CDCl3): δ = 166.4, 137.9, 135.2, 133.2, 132.2, 131.9, 128.7, 128.6, 127.4, 127.3, 127.2, 126.9, 126.3, 126.2, 125.8, 125.3, 122.8, 122.5, 118.3, 117.4, 113.1, 51.4, 39.8. HRMS (ESI): m/z [M + Na]+ calcd for C47H32Cl2N2NaO4 +: 781.1631; found: 781.1622. Compound 3l White solid, 37.4 mg, 44%; purified by a silica gel flash chromatography (hexane/EtOAc, 17:3). 1H NMR (400 MHz, CDCl3): δ = 8.34 (d, J = 7.9 Hz, 2 H), 7.69 (s, 1 H), 7.52–7.35 (m, 15 H), 7.34–7.27 (m, 2 H), 7.18 (d, J = 7.9 Hz, 2 H), 7.16–7.11 (m, 2 H), 6.92 (t, J = 8.1 Hz, 2 H), 3.27 (s, 6 H). 13C NMR (100 MHz, CDCl3): δ = 166.5, 137.6, 136.2, 130.6, 130.3, 129.9, 128.7, 128.6, 128.5, 128.2, 127.7, 127.4, 127.3, 126.5, 125.0, 124.9, 123.9, 122.4, 121.8, 119.7, 119.1, 111.4, 51.4, 39.7. HRMS (ESI): m/z [M + Na]+ calcd for C47H32Br2N2NaO4 +: 869.0621; found: 869.0630. Compound 3m Pale yellow solid, 22.3 mg, 26%; purified by a silica gel flash chromatography (hexane/EtOAc, 4:1). 1H NMR (400 MHz, CDCl3): δ = 7.38–7.35 (m, 8 H), 7.29–7.25 (m, 1 H), 7.17 (s, 1 H), 7.15 (d, J = 8.7 Hz, 2 H), 6.88–6.81 (m, 2 H), 6.61 (s, 2 H), 6.39 (s, 2 H), 4.02 (d, J = 2.8 Hz, 2 H), 3.92 (q, J = 7.0, 6.6 Hz, 2 H), 3.81 (s, 6 H), 3.79 (s, 3 H), 3.29 (s, 6 H), 3.26 (s, 6 H), 2.96–2.86 (m, 4 H). 13C NMR (100 MHz, CDCl3): δ = 166.6, 158.4, 147.3, 147.1, 136.7, 133.7, 131.3, 130.5, 129.5, 128.1, 126.6, 126.0, 124.5, 121.4, 120.7, 114.0, 113.8, 110.6, 107.9, 55.9, 55.3, 55.0, 51.0, 42.1, 39.7, 29.1. HRMS (ESI): m/z [M + Na]+ calcd for C52H48N2NaO9 +: 867.3252; found: 867.3260.